IgA is the predominant immunoglobulin isotype found in external secretions, including tears, saliva, colostrum and milk, respiratory, gastrointestinal, and genito-urinary secretions. In fact, although IgA is not found in high levels in the blood, its daily production exceeds production of all other isotypes. Secretory IgA production and secretion may be stimulated when an antigen is ingested or inhaled. The antigen penetrates mucosal epithelium and sensitizes, via T cells, antigen-specific B cells. The sensitized B cells then move out of the local site and migrate (via the thoracic duct) to the general circulation, eventually homing to distant mucosal sites and differentiating in the process. Thus, antigen encountered at one site stimulates dissemination of an IgA-mediated response to distal sites. The end result is prevention of infectious disease contracted through the large area of mucosal surfaces and inhibition of uptake of potentially allergenic environmental substances.
Serum IgA is predominantly monomeric, consisting of two H and two L chains (i.e., two binding sites) (see J. Mestecky and J. R. McGhee, "Immunoglobulin A (IgA): Molecular and Cellular Interactions Involved in IgA Biosynthesis and Immune Response," Advances in Immunology 40:153-245). In contrast, mucosal secretions contain polymeric forms of IgA (largely dimers) with attached J chains and secretory components (SC). Polymerization is initiated through incorporation of the J chain within the B cell. Following secretion from the B cell, polymeric IgA is taken up by SC on the basolateral surface of mucosal epithelial cells, endocytosed, transported through the epithelial cell, and released into the mucosal lumen with SC attached. The SC functions not only in transporting IgA to secretions, but also protects IgA from proteolytic cleavage.
IgA fulfills a critical protective role against the constant environmental insults encountered at mucosal surfaces (B. J. Underdown and J. M. Schiff, Ann. Rev. Immunol. 4:489-417, 1986). Although the mechanism of protection is not completely defined, the IgA-mediated mucosal immune response may be at least partially manifested through binding of IgA-coated targets to Fc receptors on effector cells. In particular, monocytes, macrophages, neutrophils, and myeloid cell lines have been shown to express cell surface IgA Fc receptors (Fc.alpha.R) (see M. W. Fanger et al., Proc. Natl. Acad. Sci. 77:3640-44, 1980; J. Gauldie et al., Molec. Immunol. 20:1029-37, 1983; C. R. Maliszewski et al., J. Immunol. 135:3878-81, 1985; and A. Chevalier et al., J. Immunol. 142:2244-49, 1989), which mediate effector functions such as phagocytosis (see M. W. Fanger et al., Molec. Immunol. 20:1019-27, 1983; L. Shen et al., Molec. Immunol. 23:611-18, 1986), antibody-dependent cell cytotoxicity (L. Shen and M. W. Fanger, Molec. Immunol. 59:75-81, 1981), and inflammatory mediator release (N. R. Ferreri et al., J. Immunol. 136:4188-93, 1986). Other studies indicate that the human myeloid cell Fc.alpha.R is a heterogeneously charged, .about.60-kD molecule which, upon deglycosylation, can be resolved to two protein cores of 32- and 36-kD (M. Albrechtson et al., Immunology 64:201-205, 1988; and R. C. Monteiro et al., J. Exp. Med. 171:597-613, 1990).
The present invention provides membrane bound and soluble forms of a mammalian Fc receptor for IgA, and further provides other related advantages.